Lilja-Fischer Jacob, Horsholt Kristensen Morten, Lassen Pernille, Steiniche Torben, Tramm Trine, Stougaard Magnus, Frederiksen Anders, Ulhøi Benedicte, Alsner Jan, Toustrup Kasper, Maare Christian, Johansen Jørgen, Primdahl Hanne, Andrup Kristensen Claus, Andersen Maria, Grau Eriksen Jesper, Overgaard Jens
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark; Department of Otolaryngology - Head & Neck surgery, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Health, Aarhus University, Denmark. Lilja-Fischer
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
Acta Oncol. 2025 Aug 26;64:1129-1135. doi: 10.2340/1651-226X.2025.44042.
This study investigated prognostic biomarkers in oropharyngeal squamous cell carcinoma (OPSCC), with a focus on tumors related to human papillomavirus (HPV) infection and potential molecular effects of tobacco smoking, as smokers with HPV+ OPSCC often have poorer outcomes.
PATIENTS/MATERIAL AND METHODS: We first analyzed 56 previously untreated OPSCC patients (exploration cohort), assessing HPV status, gene expression related to hypoxia, tumor subtype, and radiosensitivity, together with next-generation sequencing (NGS) of cancer-related genes. A custom NGS panel was subsequently designed and validated in 162 patients from the DAHANCA 19 randomized controlled trial (RCT), all treated with curative (chemo-)radiotherapy.
In the exploration cohort (40 HPV+, 79%), the most common molecular events in HPV+ tumors were PIK3CA and ATR mutations and chromosome 3q amplification. ATR and CREBBP mutations occurred more often in heavy smokers (>10 pack-years), but these associations were not confirmed in the DAHANCA 19 cohort. No specific smoking-related mutational signature or link to TP53 mutations was observed. In the DAHANCA 19 cohort, 17 locoregional failures (LRF) occurred among 128 HPV+ patients. No unifying molecular features were identified. However, mutations in NFE2L2 and CASP8, as well as amplifications of 3q genes (BCL6, SOX2), were associated with LRF.
In HPV+ OPSCC, only few molecular alterations appear to act as drivers or prognostic biomarkers. Importantly, no molecular features of tobacco smoking exposure were identified, and the mechanism behind the worse prognosis in smokers remains unclear.
本研究调查口咽鳞状细胞癌（OPSCC）的预后生物标志物，重点关注与人乳头瘤病毒（HPV）感染相关的肿瘤以及吸烟的潜在分子效应，因为HPV阳性的OPSCC吸烟者往往预后较差。
患者/材料与方法：我们首先分析了56例先前未接受治疗的OPSCC患者（探索队列），评估HPV状态、与缺氧相关的基因表达、肿瘤亚型和放射敏感性，以及癌症相关基因的二代测序（NGS）。随后设计了一个定制的NGS检测板，并在来自DAHANCA 19随机对照试验（RCT）的162例患者中进行了验证，所有患者均接受了根治性（化疗）放疗。
在探索队列中（40例HPV阳性，占79%），HPV阳性肿瘤中最常见的分子事件是PIK3CA和ATR突变以及3号染色体q臂扩增。ATR和CREBBP突变在重度吸烟者（>10包年）中更常见，但这些关联在DAHANCA 19队列中未得到证实。未观察到与吸烟相关的特定突变特征或与TP53突变的联系。在DAHANCA 19队列中，128例HPV阳性患者中有17例发生了局部区域复发（LRF）。未发现统一的分子特征。然而，NFE2L2和CASP8突变以及3q基因（BCL6、SOX2）的扩增与LRF相关。
在HPV阳性的OPSCC中，似乎只有少数分子改变可作为驱动因素或预后生物标志物。重要的是，未发现吸烟暴露的分子特征，吸烟者预后较差的背后机制仍不清楚。
